Non-invasive in vivo assessment of 11β-hydroxysteroid dehydrogenase type 1 activity by 19F-Magnetic Resonance Spectroscopy

• Published in: Scientific reports 2022-09, Vol.12 (1), p.16268-16268, Article 16268
• Main Authors: Naredo-Gonzalez, Gregorio, Upreti, Rita, Jansen, Maurits A., Semple, Scott, Sutcliffe, Oliver B., Marshall, Ian, Walker, Brian R., Andrew, Ruth
• Format: Article
• Language: English
• Subjects: 11β-Hydroxysteroid dehydrogenase; 639/638; 639/638/11/878; 692/163; 692/163/2743/137; 692/308/2778; 692/53; Cognitive ability; Dehydrogenase; Dehydrogenases; Dexamethasone; Diabetes mellitus; Glucocorticoids; Humanities and Social Sciences; Liver; Magnetic resonance spectroscopy; multidisciplinary; Oral administration; Pharmacodynamics; Science; Science (multidisciplinary); Spectroscopy; Spectrum analysis; Steroid hormones; Tracers; Translation
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-18740-5

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies tissue glucocorticoid levels and is a pharmaceutical target in diabetes and cognitive decline. Clinical translation of inhibitors is hampered by lack of in vivo pharmacodynamic biomarkers. Our goal was to monitor substrates and products of 11β-HSD1 non-invasively in liver via 19 Fluorine magnetic resonance spectroscopy ( 19 F-MRS). Interconversion of mono/poly-fluorinated substrate/product pairs was studied in Wistar rats (male, n = 6) and healthy men (n = 3) using 7T and 3T MRI scanners, respectively. Here we show that the in vitro limit of detection, as absolute fluorine content, was 0.625 μmole in blood. Mono-fluorinated steroids, dexamethasone and 11-dehydrodexamethasone, were detected in phantoms but not in vivo in human liver following oral dosing. A non-steroidal polyfluorinated tracer, 2-(phenylsulfonyl)-1-(4-(trifluoromethyl)phenyl)ethanone and its metabolic product were detected in vivo in rat liver after oral administration of the keto-substrate, reading out reductase activity. Administration of a selective 11β-HSD1 inhibitor in vivo in rats altered total liver 19 F-MRS signal. We conclude that there is insufficient sensitivity to measure mono-fluorinated tracers in vivo in man with current dosage regimens and clinical scanners. However, since reductase activity was observed in rats using poly-fluorinated tracers, this concept could be pursued for translation to man with further development.